Although most HIV-infected subjects have a high frequency of HIV-specific CD8 T lymphocytes, the targeted immune response fails to control HIV production. This suggests that the function of antiviral CD8 T cells, important in the control of most viral infections, is impaired in vivo in HIV-infection. Peripheral blood cells freshly isolated from HIV-infected donors frequently lack detectable HIV-specific cytotoxicity. Preliminary studies suggest that lack of protective CD8 T cell-mediated immunosurveillance could be due to defects in T cell signaling, lack of expression of the key cytolytic effector molecule perforin, or to inefficient trafficking to lymphoid sites of HIV infection. HIV-specific CD8 T cells stained with MHC-peptide tetramers have down-modulated the key T cell signaling molecules CD3C; and CD28, frequently do not express perforin, and do not express the molecules required for efficient trafficking to lymphoid tissue. Moreover, cells with down-modulated CD3< do not express the high affinity IL-2 receptor or produce IL-2 after activation. In more advanced patients, the level of CD8 T cell dysfunction may be more severe. The proportion of CD8 T cells with down-modulated CD34 is greater and does not reverse with IL-2, as it does in less advanced donor samples. Moreover, CD8 T cell activation and IFNy production in response to HIV-infected CD4 T cells in advanced patients does not occur unless exogenous IL-2 is provided. The goal of this proposal is to sort out the relative importance of each of these possible impediments to CD8 T cell control of HIV infection and determine whether they are part of normal immune regulation, secondary to chronic antigenic stimulation or inflammation, or specific to HIV infection. In particular, CD8 T cells specific for HIV will be compared to those specific for a self-limited infection and other chronic infections in normal and HIV-infected donors. The properties of HIV-specific CD8 T cells in the blood and in the lymphoid tissues will also be compared. CD8 T cell function and characteristics will be analyzed at different stages of disease, with special emphasis on a comparison between early stage donors with and without intact proliferative responses to HIV gag to test the hypothesis that deficiencies in CD4 helper cell function are responsible for the lack of protective CD8 T cell function. In vitro experiments will be performed to dissect the relative importance of signaling and perforin defects in impaired HIV-specific cytotoxicity and to explore what factors regulate and can reverse impaired CD8 T cell function.